Lauren Albin & Josh Nesbit
HumBio 153: Parasites and Pestilence
Training, distribution, and evaluation for a rapid diagnostic test (RDT) program for malaria diagnosis in rural Malawi
Malaria is currently one of the major causes of morbidity and mortality in Africa. The disease accounts for 10% of the continentÕs disease burden1 and is the leading cause of under-5 mortality2. Although strategies currently exist for treatment and prevention of malaria in endemic regions, close-to-home approaches to malaria diagnostics are severely lacking3. This particularly affects access to malarial health care for poor, rural populations in African nations like Malawi that lack the resources and infrastructure necessary to mount a successful campaign against malaria. Rapid diagnostic tests (RDTs) represent an accurate alternative in regions where microscopy is not an available or practical method of diagnosis. Evaluation and implementation of accessible, accurate methods of diagnostics may prove valuable in improving both access to treatment and clinical outcome for vulnerable groups as well the population at large. We propose an RDT Training and Distribution Program for community health workers (CHWs) in the St. GabrielÕs HospitalÕs catchment area. This program will aid in the hospitalÕs management of malariaÕs disease burden in the rural catchment area.
The Rapid Diagnostic Test (RDT) Training Program has very specific goals, which are vital to the success of the RDT Distribution Program. These goalsa are enveloped by the following benchmarks:
1. The CHWs are able to describe RDTs, and understand what actions to take upon completion of positive and negative tests
2. The CHWs understand how to properly use the RDTs
3. The CHWs are able to safely draw blood, using a finger prick
4. The CHWs are able to use the attached visual aid to administer a diagnostic test
5. The CHWs are able to identify and explain each possible test result (positive, negative, or invalid)
Building on the RDT Training ProgramÕs goals, the aims of the RDT Distribution Program include:
1. Providing CHWs with adequate RDT supplies
2. Ensuring the RDT supplies are accessible to the populations served by each CHW
3. The CHWs successfully use RDTs in the field and at the testing site
These specific aims of the RDT Program must be realized in order for the training and distribution to be considered successful. Without imparting testing knowledge, technique, and confidence through hands-on practice, the usefulness of widespread RDT distribution will not be demonstrated. Further, without proper and complete distribution, coupled with true testing experience, the training program will be for naught.
Epidemiology and Disease Burden:
Malaria is highly prevalent worldwide, with up to 3.2 billion people at risk and an annual incidence of approximately 500 million cases. Regional distribution is generally limited to parts of Africa, South America, and Asia due to the need for tropical temperatures for parasite development and adequate rainfall to supply breeding grounds for the Anopheles hosts. Malawi, located on the southern end of the east African Rift, is home to several malarial parasite species, the most common (and deadly) being Plasmodium falciparum5. Primary vectors in the region are Anopheles gambiae and Anopheles funestus. 100% of the nationÕs population is considered to be at risk for infection with seasonal transmission varying according to geographic region. Children and pregnant women remain at highest risk. In the early 2000s, malaria accounted for approximately one fourth of all hospital admissions and hospital deaths5 in the country, although these numbers are thought to be drastic underestimates due to additional outpatient presentations and cases that never actually present at medical facilities. In addition to high mortality, economic losses due to malarial infection are also severe. Infected adults lose an average of 25 days of work per year, leading to decreased national productivity and family income5. Medical costs of infection can also create an additional burden on family finances. Preventative management and treatment are both limited in scope, often due access issues.
Transmission of malaria requires interaction between the two separate host species: female Anopheles mosquitoes, which are definitive hosts for the parasite, and humans which serve as intermediate hosts. The asexual cycle of the parasites begins in humans when sporozoites invade the liver after being injected from a mosquito during a blood meal. Once in the liver, the sporozoites undergo schizogonyb over a period of 6-15 days and become merozoitesc. Merozoites invade red blood cells and begin an erthrocytic schizogony cycle which produces new merozoites to further invade red blood cells. Some merozoites will differentiate into gametocytesd that can be ingested by a new mosquito during a blood meal. Once the gametocytes enter the mosquito, the sexual cycle begins. Gametocytes mature in female and male gametes and fertilization occurs in the midgut of the insect. Sporozoites emerge after 10-18 days and migrate to the salivary glands to later be injected into a new human host. Transmission therefore requires that the mosquito survive long enough for reproduction to occur and takes at least one more blood meal after new sporozoites emerge. Blood stage parasites in humans are those that typically cause clinical symptoms of malaria. Invading merozoites in red blood cells can result in severe problems including anemia and cytoadherence. (Figure 1e)
Rapid Diagnostic Tests
The development of increasingly accurate Rapid Diagnostic Tests (RDTs) offers an alternative method of diagnosis that may be more applicable in rural Malawi. RDTs come in prepackaged kits that include detailed instructions, require no additional laboratory equipment or capital investment and are easy to interpret, making them useful to community health workers (CHWs) with little advanced medical training7. With proper implementation, CHWs utilizing RDTs could make close-to-home diagnosis available in community settings, thus improving the possibility for timely treatment and management of the disease.
RDTs are designed to detect antigens produced by malaria parasites in a small amount of blood (usually 5–15 µL) of infected humans. The RDT is composed of a nitrocellulose strip and dye-labeled antibody that is specific for the target antigen (typically designed according to local malaria epidemiology). Most RDTs only detect P. falciparum; however, some are available that can distinguish P. falciparum from non-falciparum species. The dye-labeled antibodies bind to parasite antigen which is released from red blood cells upon lysing by an added reagent. Upon addition of a buffer solution, the dye-labeled antibodies are then captured on the test strip resulting in a visible line indicating that the individual is positive for infection7. The test line will vary in intensity depending on the antigen density (parasitic load) in the blood. Results are typically visible within fifteen minutes and blood samples are commonly obtained with a simple finger prick. (Figure 2f)
Accuracy of RDTs is still dependent on correctness of preparation and interpretation of the tests and can vary greatly according to the user8. According to the WHO, instruction manuals (also called job-aids) that accompany all RDTs were designed with the specific aim of improving accuracy and safety of the tests, and should ideally be in the native language of the community health workers using them7. A study on RDT error conducted in the Philippines concluded that errors could be minimized with the provision of such instructions and that a short orientation on RDT use could further improve accuracy by another 10%8.
Newly developed RDTs generally have high enough sensitivities to be useful diagnostically. A study conducted in Thailand indicated that P. falciparum specific RDTs have sensitivities approaching 100%, although RDT sensitivity typically declines at parasite densities < 500/mcL blood for P. falciparum and < 5,000/mcL blood for P. vivax9. Sensitivity in detecting other Plasmodium species varies by RDT type but is typically lower than for P. falciparum, possibly indicating a primary usage of RDTs in P. falciparum endemic areas. False positives occur in only a small percent of tests, sometimes due to the presence of rheumatoid factor in the blood or due to environmental conditions outside the RDT optimal temperature (4-30” C) and humidity ranges. Direct comparison of RDTs with microscopy techniques has proved difficult due to varying reference standards and differing epidemiological and clinical characteristics of potential study populations9.
Additional analyses have indicated that the cost effectiveness of RDTs can vary with regional malaria prevalence, RDT cost, price of anti-malarial treatment, and the cost of treatment of other illnesses when malaria has been ruled out9. Essentially, RDTs are thought to become more cost effective as the price of anti-malarials increases. The price of a single RDT depends on the total order quantity and number of species the RDT targets, but typically ranges from US $0.55 – US $1.50 in developing countries.
St. GabrielÕs Hospital and Malaria Obstacles
Unfortunately, early diagnosis remains one of the major obstacles limiting effective malaria management in the area served by St. GabrielÕs. Clinical diagnosis is the most commonly used and least expensive method; however, the overlapping of malaria symptoms with other tropical diseases impairs its specificity9. More accurate malaria diagnosis is largely reliant upon microscopy or PCR methods, both of which require expensive laboratory equipment and experienced technicians. Unfortunately, the limited number of trained health workers available in Malawi has placed tremendous pressure on Malawian health services, including St. GabrielÕs Hospital, to compensate for lack of medical manpower. The deficiency of trained medical staff at St. GabrielÕs and in other limited-resource settings makes microscopy and PCR-based diagnostic techniques difficult to utilize.
The World Health Organization (WHO) recommends that health services employ a bare minimum of 100 nurses and 20 doctors per 100,000 people12. Current statistics show 56 nurses and 2 doctors per 100,000 Malawians13. This need for trained medical professionals is resonated by the staffing situation at St. GabrielÕs – there are two MDs, eight trained nurses, and five clinical officers (whoÕve completed two years of technical training) responsible for the health care of 250,000 individuals. Due to the harsh staffing situation, St. GabrielÕs must follow a current trend in limited-resource settings facing large disease burdens14– shifting healthcare services to trained community health workers (CHWs). This is precisely the objective of the proposed RDT Training and Distribution Program.
Shifting diagnostic testing services to CHWs, spread throughout the catchment area, will strengthen the hospitalÕs ability to manage malariaÕs disease burden. Without early diagnosis, the potential for rational therapy of malaria is severely compromised, a factor which critical evaluation of disease management indicates is imperative to delay the development of resistance as well as to save cost on alternative drugs9. Thus, in order to offset further malaria burden in the hospitalÕs catchment area, obtainable diagnostic methods need to be implemented to increase health status availability, create patient referral networks, and provide more accurate prevalence and incidence data.
Phase I: Meetings with St. GabrielÕs Hospital and the Village AIDS Committee (VAC)
The initial step of the RDT Program will be to introduce the programÕs goals to St. GabrielÕs Hospital. In this introduction, feedback will be recorded, and programmatic details adjusted accordingly. For example, the hospital will inform the RDT instructors regarding necessary actions that should be taken once a patient is tested positive or negative. The instructions will be finalized and integrated into the RDT Training Program for the CHWs, with a goal of homogenizing the RDT ProgramÕs goals with hospital protocol and national malaria diagnosis and treatment guidelines.
The VAC, which coordinates the CHWsÕ activities and centralized meetings, will be an essential partner in implementing the Training and Distribution programs. We will meet with the VAC to discuss project goals, before any training or distribution commences.
Phase II: RDT Training Program; CHW Training
The RDT Training Program will seek to accomplish the five goals listed above, through careful instruction and practice. Instructors will utilize a designated RDT test that is best suited for the epidemiological area, and an RDT training guide created by the World Health Organization (WHO) and the United States Agency for International Development (USAID) for training at a village and clinic level (attached). The training guide will be supplemented by a visual RDT instruction aid, also developed by the WHO (attached).
Employing the organizational capacity of the VAC, CHWs will meet in a centralized location for training. Training sessions will take place over a span of five weeks – one, 3-hour session, every other day. A maximum of 15 CHWs will attend each training session, so that the learning experience is confined to a small group. By the end of the five-week period, each of the hospitalÕs 200 CHWs will accomplish the five training goals.
Phase II: RDT Training Program; Clinician Training and Education
In order for the RDT Program to be successful, CHW RDT training and RDT distribution must be coupled with education of clinical staff providing antimalarial medication15. Current diagnostic methods are based on clinical symptoms - many patients presenting with febrile illness receive antimalarials, without diagnostic confirmation of malaria infection. Educational sessions with hospital staff will provide a similar RDT training session for the clinical staff (3-hour session, following the WHO training guide), but will also highlight the significance that positive and negative RDT results have for the procurement of antimalarial drugs.
Phase III: RDT Distribution Program
After the four-week training program is complete, testing supplies will be distributed. These supplies will include testing kits, copies of the instruction manual, visual testing aids, notebooks for anonymous record keeping, and forms for hospital referral (should St. GabrielÕs determine that referral is the best course of action for RDT-positive patients).
Phase IV: Evaluation of the RDT Program Components
The success of the meetings with St. GabrielÕs and the VAC will be largely evaluated by the extent to which their respective ideas are incorporated into the training and distribution program, and the ability to establish partnerships.
Evaluation of the RDT Training Program, along with the RDT Distribution Program, will be completed by observing CHWs administering RDTs, examining the record books (which will document the number of patients tested at each site), and monitoring the hospital referral system. Finally, community focus groups and semi-structured interviews with community members regarding their interaction with testing services will be used to gauge the programÕs success. The combination of quantitative and qualitative results will allow for future expansion and betterment of the RDT Program.
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a Adapted from Learning Objectives: How to use a rapid diagnostic test (RDT): A guide for training at a village and clinic level. 2006. The Quality Assurance Project (QAP) and the World Health Organization (WHO), Bethesda, MD, and Geneva. This manual is attached.
b Shizogony is a form of asexual reproduction in which the nucleus divides before actual cell division (cell divides into as many parts as there are nuclei).
c Merozoites are products of schizogony which can infect new host cells.
d Gametocytes can eventually develop into gametes.
e Schema of the Lifecycle of Malaria. CDC. Department of Health and Human Services. < http://www.cdc.gov/malaria/biology/life_cycle.htm>.
f Making Rapid Diagnosis Work. Malaria Rapid Diagnostic Tests. World Health Organization Regional Office for the Western Pacific. 2005. <http://www.wpro.who.int/sites/rdt>.